New pharmacologically active esters of n-(3-trifluoromethylphenyl)-anthranilic acid

ABSTRACT

OR A LOWER ALKYL GROUP HAVING UP TO THREE CARBON ATOMS IN WHICH ONE OR TWO HYDROGEN ATOMS ARE REPLACED BY HYDROXYL GROUPS, ACYLOXY GROUPS HAVING UP TO FOUR CARBON ATOMS, OR LOWER HYDROXYALKOXY GROUPS, HAVING AN ANTIFLAMMATORY ACTION.   IN WHICH R represents the radical   Compounds of the general formula:

United States Patent Boltze et al.

[ Sept. 19, 1972 NEW PHARMACOLOGICALLY ACTIVE ESTERS OF N-(3- TRIFLUOROMETHYLPHENYL)- ANTHRANILIC ACID [72] Inventors: Karl-Heinz Boltze, Bensberg-Kippekausen; I Otfried Brendler, Cologne, Mulheim; Dietrich Lorenz, Bensberg, all of Germany [73] Assignee: Troponwerke Dinklage 8: Co.,

Cologne-Mulheim, Germany [22] Filed: July 16, 1970 [21] Appl. No.: 55,563

[30] Foreign Application Priority Data Aug. 1, 1969 Germany ..P 19 39 112.9

[52] US. Cl. ..260/471 R, 424/309 [51] Int. Cl ..C07c 101/54 [58] Field of Search ..260/471 R [56] References Cited OTHER PUBLICATIONS Wagner; R. B., Syn. Org. Chem. (1967), Pub. by John Wiley and Sons, Inc. (QD 262W24), page 484 Relied Primary ExaminerLorraine A. Weinberger Assistant Examiner-L. Arnold Thaxton Attorney-Burgess, Dinklage & Sprung [5 7] ABSTRACT Compounds of the general formula:

CFa

or a lower alkyl group having up to three carbon atoms in which one or two hydrogen atoms are replaced by hydroxyl groups, acyloxy groups having up to four carbon atoms, or lower hydroxyalkoxy groups, having an antiflammatory action.

7 Claims, N0 Drawings NEW PHARMACOLOGICALLY ACTIVE ESTERS OF N-(3-TRIFLUOROMETHYLPHENYL)- ANTHRANILIC ACID This invention relates to new pharmacologically active esters of N-(3-trifluoromethylphenyl)-anthranilic acid and process for their preparation.

The invention provides compounds of the general formula 1:

i -CFa in which R represents a radical 11:

or a lower alkyl group having up to and including three carbon atoms in which one or two hydrogen atoms are replaced by hydroxyl groups, acyloxy groups having up to and including four carbon atoms or lower hydroxyalkoxy groups.

These lower hydroxyalkoxy groups which may be present preferably contain up to and including four carbon atoms and up to and including three hydroxyl groups.

It is known that N-(3-trifluoromethylphenyl)- anthranilic acid (hereinafter to be referred to as [11) has a marked antiinflammatory action (see WINDER et al., Arthrit. Rheumat. 6, 36-47 (1963) or D.E. BARNAR- DO et al., Brit. medJ. 1966 11, pages 342-343). The strongly acid properties of this compound, which may cause disturbances of the gastrointestinal tract, represent a disadvantage to the use of this compound. It has therefore already been proposed to use the aluminium salt instead of the free acid (see French Pat. No. 1,424,797). Another disadvantage is that for local application the free acid cannot be used in the form of a gel as the ionogenically active substances prevent gel formation.

The compounds according to the invention have the advantage over 111 that while having the same marked antiinflammatory action as 111 they do not cause any gastrointestinal disturbances, are also effective when administered orally and moreover can be worked up into gels.

in addition, they have a considerably wider therapeutic range than 111 since the LD values are about 1.5 to 3 times higher than those of 111. The positive protein turbidity test of MlZUSHlMA (see Arch. int. Pharmacodyn. 157 (1965), page 115 et seq.) moreover shows that the compounds develop their own activity and their effect is not due only to the hydrolysis of I which takes place in the body.

Preparation of the compounds according to the invention of the general formula I is carried out by reacting a metal salt, preferably an alkali metal salt, of N-(3- trifluoromethylphenyl)-anthranilic acid with compounds of the general formula EXAMPLE 1 2-(2-Hydroxyethoxy)-ethyl ester trifluoromethyl-phenyl)-anthranilic acid.

16.0 g (0.05 mol) of the potassium salt of N-(3- trifluoromethylphenyl)-anthranilic acid are dissolved of N-(3- in 60 ml of dimethylformamide and heated to C,

and 6.2 g (0.05 mol) of 2-(2-chloroethoxy)-ethanol are slowly added. The reaction mixture is then heated to boiling for 2 hours. The precipitated potassium chloride is filtered off and the solvent is removed by evaporation. The residue is separated over a column with 400 g of silica gel (particle size 0.05 to 0.2 mm), using a 1:1 mixture of cyclohexane and glacial acetic acid as eluting agent. 16.0 g of the 2-(2-hydroxyethoxy)-ethyl ester of N-(3-trifluoromethylphenyl)- anthranilic acid are obtained in the form of a pale yellow oil which does not crystallize and cannot be distilled.

Calculated: C 58.51% H 4.92%; N 3.79%;

Found: C 55.37%; H 4.87%; N 3.71%.

The following compounds were prepared by the same method:

EXAMPLE 2 EXAMPLE 3 2-(2acetoxyethoxy)-ethyl ester trifluoromethyl-phenyl)-anthranilic acid.

From 18.9 g of the potassium salt of N-(3- trifluoromethylphenyl)-anthranilic acid and 10.0 g of of N-(3- 2-(2-chloroethoxy )-ethyl acetate. Pale Yellow oil; yield 14.7 g (59.5% ofthe theory).

For C H F NO I Calculated: C 58.39%; H4.90%; N 3.41%; Found: C 58.21%; H 4.91%; N 3.41%.

EXAMPLE 4 2-(2,3-Dihydroxy-propoxy)-ethyl ester of trifluoromethyl-phenyl)-anthranilic acid.

63.8 g (0.2 mol) of the potassium salt of N-(3- trifluoromethylphenyl)-anthranilic acid and 27.8 g (0.18 mol) of 2-(2,3-dihydroxy-propoxy)-ethyl chloride are dissolved in 50 ml of dimethylformamide and heated to 80 C with stirring for 3 hours. After removal of the solvent by evaporation, the residue is separated over a column with 400 g of silica gel (particle size 0.05 to 0.2 mm), using acetone and acetone/ethylene chloride 1:1 as eluting agent. 28 g of 2-(2,3-dihydroxy-propoxy)-ethyl ester of N-(3- trifluoromethylphcnyl)-anthranilic acid are obtained.

Calculated: C 57.13%; H 5.05%; N 3.50%;

Found: C 57.36%; H 5.16%; N 3.48%.

EXAMPLE 5 2-{ 3-[N-( 3-trifluoromethylphenyl)-anthrani1oyloxy]-2- hydroxypropoxy -ethyl ester of N-( 3- trifluoromethylphenyl)-anthranilic acid.

The compound is obtained as a viscoussubstance by chromatography, using the method of preparation described in Example 4. The yield is 8g.

Calculated C 59.80%; 114.28%; N 4.23%;

Found: C 59.94%; H 4.56%; N 4.29%.

What is claimed is:

1. Compounds of the general formula:

in which R represents the radical trifluoromethyl-phenyl ant hranilic acid The compound 0 claim 1 which 18 2-(2-acetoxyethoxy)-ethyl ester of N-(3-trifluoromethylphenyl)- anthranilic acid.

6. The compound of claim 1 which is 2-(2,3- Dihydroxy-propoxy )-ethyl ester of N-( 3- trifluoromethylphenyl)-anthranilic acid.

7. The compound of claim 1 which is 2-l3-[N-(3- trifluoromethylphenyl)-anthraniloyloxyI-Z-hyclroxypropoxyl-ester of N-(3-trifluoromethylphenyl)- anthranilic acid.

UNITED STATES PATENT OFFICE Certificate Patent No. 3,692,818 Patented September 19, 197 2 KarLI-Ieinz Boltze, Otfried Brendler, and Dietrich Lorenz Application having been made by Karl-Heinz Boltze, Otfried Brendler, and Dietrich Lorenz, the inventors named in the patent above identified, and Troponwerke Dinklage & 00., a corporation of Germany, the assignee, for the issuance of a certificate under the provisions of Title 35, Section 256, of the United States Code, deleting the name of Otfried Brendler as a joint inventor, and a showing and proof of facts satisfying the requirements of the said section having been submitted, it is this 27th day of November 1973, certified that the name of the said Otfried Brendler is hereby deleted ilfrom the said patent as a joint inventor With the said Karl-Heinz Boltze and Dietrich orenz.

FRED V. SuEnLINo, Associate Solicitor. 

2. Compounds as claimed in claim 1 in which the lower hydroxyalkyl groups contain up to four carbon atoms and up to three hydroxyl groups.
 3. The compound of claim 1 which is 2-(2-Hydroxy-ethoxy)-ethyl ester of N-(3-trifluoromethylphenyl)-anthra-nilic acid.
 4. The compound of claim 1 which is 2-(2-(2-hydroxyethoxy)-ethoxy)-ethyl ester of N-(3-trifluoromethyl-phenyl)-anthranilic acid.
 5. The compound of claim 1 which is 2-(2-acetoxyethoxy)-ethyl ester of N-(3-trifluoromethylphenyl)-anthranilic acid.
 6. The compound of claim 1 which is 2-(2,3-Dihydroxy-propoxy)-ethyl ester of N-(3-trifluoromethylphenyl)-anthranilic acid.
 7. The compound of claim 1 which is 2-(3-(N-(3-trifluoromethylphenyl)-anthraniloyloxy)-2-hydroxypropoxy)-ester of N-(3-trifluoromethylphenyl)-anthranilic acid. 